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Re: Targeting the Regulation of Androgen Receptor Signaling by the Heat Shock Protein 90 Cochaperone FKBP52 in Prostate Cancer Cells
1128
URO-SCIENCE
finding that P-Rex1 gene expression is subject to HDAC mediated regulation extends the understanding of the essential role of P-Rex1 in physiological and pathological situations. Also, the data suggest that disassociation of HDACs from Sp1 on the P-Rex1 promoter may contribute to aberrant up-regulation of P-Rex1 in metastatic prostate cancer. Anthony Atala, M.D.
Re: Targeting the Regulation of Androgen Receptor Signaling by the Heat Shock Protein 90 Cochaperone FKBP52 in Prostate Cancer Cells J. T. De Leon, A. Iwai, C. Feau, Y. Garcia, H. A. Balsiger, C. L. Storer, R. M. Suro, K. M. Garza, S. Lee, Y. S. Kim, Y. Chen, Y. M. Ning, D. L. Riggs, R. J. Fletterick, R. K. Guy, J. B. Trepel, L. M. Neckers and M. B. Cox Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, Texas Proc Natl Acad Sci U S A 2011; 108: 11878 –11883.
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation. Editorial Comment: Androgens are a major stimulator of prostate tumor growth, and all current therapies act as classic antagonists by competing with androgens for binding the androgen receptor hormone binding pocket. This mechanism of action exploits the dependence of androgen receptors on hormone activation. However, current treatment options become ineffective in castrate resistant prostate cancer, although castrate resistant prostate cancer remains ligand/androgen receptor dependent. Drugs that target novel surfaces on the androgen receptor and/or novel androgen receptor regulatory mechanisms may provide promising alternatives for the treatment of castrate resistant prostate cancer. The authors identified a surface region on the androgen receptor ligand binding domain that, when mutated, results in a greater functional dependence on FKBP52. This motif overlaps with the recently characterized BF3 surface. The authors developed a series of small molecules that inhibit FKBP52 regulation of androgen receptor function. These agents are predicted to act via binding to the BF3 surface in the androgen receptor ligand binding domain. The most promising compound, MJC13, inhibits hormone induced androgen receptor chaperone complex dissociation and nuclear translocation, and effectively blocks androgen receptor dependent gene expression in cellular models of prostate cancer. Further studies are needed to characterize the MJC13 binding site, improve compound efficacy and improve receptor specificity. MJC13 is a novel example of an inhibitor that specifically targets the regulation of steroid hormone receptor function by an Hsp90 associated co-chaperone and thus serves as an excellent starting point for development of FKBP52 specific inhibitors to treat hormone dependent diseases. Anthony Atala, M.D.
URO-SCIENCE
finding that P-Rex1 gene expression is subject to HDAC mediated regulation extends the understanding of the essential role of P-Rex1 in physiological and pathological situations. Also, the data suggest that disassociation of HDACs from Sp1 on the P-Rex1 promoter may contribute to aberrant up-regulation of P-Rex1 in metastatic prostate cancer. Anthony Atala, M.D.
Re: Targeting the Regulation of Androgen Receptor Signaling by the Heat Shock Protein 90 Cochaperone FKBP52 in Prostate Cancer Cells J. T. De Leon, A. Iwai, C. Feau, Y. Garcia, H. A. Balsiger, C. L. Storer, R. M. Suro, K. M. Garza, S. Lee, Y. S. Kim, Y. Chen, Y. M. Ning, D. L. Riggs, R. J. Fletterick, R. K. Guy, J. B. Trepel, L. M. Neckers and M. B. Cox Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, Texas Proc Natl Acad Sci U S A 2011; 108: 11878 –11883.
Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation. Editorial Comment: Androgens are a major stimulator of prostate tumor growth, and all current therapies act as classic antagonists by competing with androgens for binding the androgen receptor hormone binding pocket. This mechanism of action exploits the dependence of androgen receptors on hormone activation. However, current treatment options become ineffective in castrate resistant prostate cancer, although castrate resistant prostate cancer remains ligand/androgen receptor dependent. Drugs that target novel surfaces on the androgen receptor and/or novel androgen receptor regulatory mechanisms may provide promising alternatives for the treatment of castrate resistant prostate cancer. The authors identified a surface region on the androgen receptor ligand binding domain that, when mutated, results in a greater functional dependence on FKBP52. This motif overlaps with the recently characterized BF3 surface. The authors developed a series of small molecules that inhibit FKBP52 regulation of androgen receptor function. These agents are predicted to act via binding to the BF3 surface in the androgen receptor ligand binding domain. The most promising compound, MJC13, inhibits hormone induced androgen receptor chaperone complex dissociation and nuclear translocation, and effectively blocks androgen receptor dependent gene expression in cellular models of prostate cancer. Further studies are needed to characterize the MJC13 binding site, improve compound efficacy and improve receptor specificity. MJC13 is a novel example of an inhibitor that specifically targets the regulation of steroid hormone receptor function by an Hsp90 associated co-chaperone and thus serves as an excellent starting point for development of FKBP52 specific inhibitors to treat hormone dependent diseases. Anthony Atala, M.D.